3-amino-2-aminomethyl-1-phenyl-1-propanols



ilnited stares Parent @i 3,058,987 S-AWO-Z-AMINGMEIHYL-I-PIENYL-l-PRGPANOLS Harry Allen Albrecht, Nntley, John Thomas Plati, Rutherford,and Wilhelm Wenuer, Upper Montclair, NJ., assrgnors to Hoifmann-La RocheTue, Nutley, NJ., a

corporation of New Jersey No Drawing. Filed Apr. 6, 1960, Ser. No.20,281 4 Claims. (Cl. 260-2947) This invention relates to derivatives ofdiamino-isobutauol. More particularly, the invention relates tocompounds which are represented by the structural formula .H .H(CH. N R(|)H \R 2 (I) wherein in the symbols R represent hydrogen, halogen,

lower alkyl or lower alkoxy and the symbols R represent lower alkylgroups or together with the nitrogen :Eorm a 5-6 membered saturatednitrogen heterocyclic,

and acid addition salts thereof.

In the formula above, either one or both of the symbols R may representhydrogen or one of the enumerated substituent groups so that either anunsubstituted phenyl group or a phenyl radical bearing one or twosubstituent groups may be present. All four halogens are included Withinthe meaning of the symbol R. The lower alkyl groups include such groupsas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl andthe like. The lower alkoxy groups include ether groups containing thesame lower alkyl radicals as above.

The group represents an acyclic or cyclic tertiary amino group. Thesymbols R may represent lower alkyl groups such as those described sothat a di-lower alkylamino radical is formed. The two symbols R may alsotogether represent a tetramethylene, pentamethylene or oxytetramethylenegroup which together with the nitrogen atom forms a 5 or 6 memberedsaturated nitrogen heterocyclic radical such as pyrrolidyl, piperidyl,morpholinyl and the like.

The compounds of the structural formula set forth above are derived fromacetophenone or halogen-, alkyl-, or alkoxy substituted acetophenones.By subjecting the acetophenone to the Mannich reaction one substitutedaminomethyl group is introduced. Repetition of the reaction underalkaline conditions effects the introduction of a second aminomethylgroup. The resulting ketone is then reduced to the alcohol of Formula I.

The first step of the procedure for forming the products of thisinvention involves reacting acetophenone or the appropriatelysubstituted acetophenone with about one molar proportion of an aminesuch as dimethylamine, pyrrolidine, piperidine, or morpholine, or anacid salt thereof, and formaldehyde or paraformaldehyde. By conductingthis reaction under acid conditions, e.g. in the presence of addedhydrochloric acid, the introduction of one aminomethyl group is favored.Generally a well crystallized material results and a convenient methodof purifying the intermediate is thus provided.

A second aminomethyl group is introduced by reacting the intermediate,substituted aminopropiophenone with a second molar proportion of thetertiary amine and formaldehyde or paraformaldehyde, this time underalkaline conditions, e.g. in the presence of sodium hydroxide or excessamine. In this manner a substituted di-aminoisobutyrophenone isobtained.

ice

The substituted di-aminoisobutyrophenone may be re duced to the alcohol,for example, with alkali metal hydrides such as sodium borohydride,preferably in an inert solvent such as alcohol.

The products of Formula I are basic compounds which form acid additionsalts by reaction with about one or two molar proportions of inorganicor organic acid. Such acid addition salts as the hydrohalides, e.g.hydrochloride, hydrobromide, hydroiodide, hydrofluoride, other mineralacid salts such as sulfate, nitrate, posphate, and the like, alkylandmono-arylsulfonates such as ethanesulfonate, toluenesulfonate,benzenesulfonate, and the like, other organic acid salts such asacetate, tartrate, malate, citrate, benzoate, salicylate, ascorbate,etc., may in this way be obtained.

The compounds of Formula I are useful as diuretics and may be used intreating cardiac conditions such as cardiac edema or in treatinghypertension. They may be administered orally by incorporating atherapeutic dosage of the base or a pharmacologically acceptable acidaddition salt in a conventional oral dosage form such as tablets,capsules, elixirs, suspensions or the like.

The following examples illustrates the invention. peratures areexpressed in degrees centr-igrade.

Tem-

Example 1 Acetophenone g.), dimethylamine hydrochloride (106 g.),paraformaldehyde (39.6 g.), ethanol ml.), and 2 m1. of concentratedhydrochloric acid were refluxed for 2 hours. After the addition of 800ml. of acetone, the product was allowed to crystallize in the cold,filtered, washed with acetone, and dried on the steam bath to obtain,B-dimethylaminopropiophenone hydrochloride, M.P. 153-455".

{3-Dimethylaminopropiophenone hydrochloride (60 g.), 37% formaldehydesolution (22.8 g.), 25% dimethylamine in water (101 g.), and 360 ml. ofethanol were refluxed 1 hour. The solvent was distilled off in vacuo.Water (300 ml.) and excess 50% sodium hydroxide solution were added. Themixture was extracted with 400 ml. of ether. After drying with anhydroussodium sulfate, the ether was evaporated in vacuo. The residual base wascrystallized from 100 ml. of petroleum ether to yield adimethylaminomethyl-fl-dimethylaminopropiophenone, M.P. 54-5 6.

a Dimethylaminomethyl-fl-dimethylaminopropiophenone dihydrochloride,M.P. 164l65, was obtained in crystalline form by adding a solution ofhydrogen chloride in ethanol to an ethanolic solution of the base.

a Dimethylaminomethyl B dimethylaminopropiophenone (26.2 g.) wasdissolved in 180 ml. of methanol and added to a solution of sodiumborohydride (4.24 g.) in 500 ml. of 50% methanol, below 10. The additionrequired 8 minutes. The mixture was stirred for 1 hour while warming toroom temperature, and then for 4 hours at 45-50. Most of the methanolwas distilled 05 in vacuo. With cooling, 150 ml. of water and 30 ml. of50% sodium hydroxide solution were added. The base was extracted with 2portions of ether (250 ml. and 150 ml). After drying over sodiumsulfate, the ether was evaporated in vacuo to yield eventually acrystalline residue. On crystallization from 50 ml. of petroleum ether,3-dimethylamino-2-dimethylaminomethyl 1 phenyl-lpropanol, M.P. 6365, wasobtained.

Addition of a solution of hydrogen chloride in ethanol to 4 g. of crudebase obtained above in 10 ml. of ethanol gave the crystallinedihydrochloride, M.P. 225-227.

Example 2 Piperidine hydrochloride (69.3 g.), acetophenone (68.4 g.),paraformaldehyde (25.7 g.) and ml. of ethanol were refluxed for 30minutes. Then, 34 g. of paraformalrefluxed for 2 hours.

dehyde was added, and refluxing continued for 17 hours.

On cooling, the product crystallized. It was filtered and washed withcold ethanol to obtain B-(l-piperidyDpropiophenone hydrochloride, M.P.178-184.

13-(l-piperidyl)propiophenone hydrochloride (53 g.),

. of ethanol and a solution of hydrogen chloride in ethanol piperidine(35.6 g.), 37% formaldehyde solution (25.4

g.), and 300 ml. of ethanol were refluxed for 1 hour. The solvent wasdistilled off in vacuo. Water (200 ml.) was added, followed by excess50% sodium hydroxide solution (50 ml.), with cooling. The :base wasextracted with 300 ml. of benzene, washed with three 100 ml. portions ofwater, and dried over sodium sulfate. After dis tillation of the benzenein vacuo, the residue was dissolved in 2 liters of ether and acidifiedby addition of 180 ml.

or a solution of hydrogen chloride in ethanol (about 3 N). 3(l-piperidyl)-2-(l-piperidylrnethyl)-1-phenyl-1- propanone hydrochlorideprecipitated as a gum. The ether 'Was decanted and 2500 ml. of hot ethylacetate was to 30 and filtered to obtain crude dihydrochloride which,onheating, softened at 120 and meltedat 143-146. Crude dihydrochloriderecrystallized from a mixture of 30 ml. of ethanol and .60 ml. of etherto give the pure product melting at 155-157.

Thebase was liberated from 40 g. of 3-(1-piperidyl)-2-(l-piperidylmethyl) 1 phcnyl 1 propanone dihydrochloride by dissolvingin 400 ml. of water and adding excess 50% sodium hydroxide solution. Theoily base was isolated by extracting w'th ether, and evaporating theether in vacuo. The base was dissolved in 150 m1. of methanol, cooled,and added to a solution of 3.91 g. of sodium borohydride in 200 ml. of50% methanol below 10. After stirring in the cold for 5 minutes,themixture was allowed to warm to room temperature during 1 hour and 50minutes. The mixture then was maintained at 45-5.0 for 2 /2 hours.Crystallization occurred on cooling. The product,3-(l-piperidyl)-2-(1epiperidy1 methyl)-1-phenyl-1-propanol, was filteredand washed with cold 50% methanol, MP. 84-86".

The base obtained above (3 g.) was dissolved in 100 ml. or dry ether,and dry hydrogen bromide was passed in to precipitate the solid salt. Oncrystallization from ethanol, pure 3-(l-piperidyl)-2-(1-piperidylmethyl)lphenyl-l-propanol dihydrobromide,M.P. 140144, was

obtained. t

Example 3 4-chloroacetophenone (46.2 g.), piperidine hydrochloride (36.4g.), paraformaldehyde'(l3.5 g.), ethanol (60 ml.) and 1 ml. ofconcentrated hydrochloric acid were On cooling, crystallinefi-(l-piperidyl)-p-chloropropiophenone hydrochloride, M.P. 19l- 192, wasobtained. I

3 (l-piperidyl)-p-chloropropiophenone hydrochloride (39.3 g.),piperidine (23.3 g.), 37% formaldehyde solution (167 g.), and 200 ml.

1 hour. The solvent was distilled ofi in vacuo. With cooling, 200 ml. ofwater and 40 ml. of 50% sodium hydroxide solution were added. Themixture was extracted with 2 portions of ether (200 ml. and 1001111.).

The combined ether extracts were dried over sodium sulfate The .etherwas evaporated in vacuo, and the residue was crystallized from a mixtureof 120 ml. of methanol and ml. of water, to obtain3-(1-piperidyl)-2-(1-piperidylrn'ethyl) 1-(4-chlorophenyl) -1-pIopanone,M1. 71-

Sodium borohydride (2.27 g.) -was dissolved in 40 ml. of 50% methanolbelow 10. 3-(1-piperidyl)-2-(l-piperidylmethyl) 1 (4- chlorophenyl )-lpropanone (20.9 g.)

added. After thorough digestion, the mixture was cooled of ethanol wererefluxed for was dissolved in 150 ml. of methanol and added withcontinned cooling below li0i After 5 minutes of stirring in the cold,the ice .bath was removed. After another 45 minutes, the mixture waswarmed at 45-50 for 45 minntes. On a cooling, the product, 3-(1-piperidyl)-2-( l-piperwas added. On dilution with ml. of ether,3-(1-piperidyl) -2-( l-piperidylmethyl') -1-(4 chloropheuyl) 1' propanoldihydrochloride, M.P. 243-245, was obtained.

Example 4 p-Methoxyacetophenone (500 g.), piperidine hydrochloride (405g.), paraformaldehyde g.), 650 ml. of ethanol, and 10 ml. ofconcentrated hydrochloric acid were refluxed for 2 hours. The productwas allowed to crystallize at room temperaturefor-Z hours and then atthe temperature of an ice bath. After filtering, washing with two 100ml. portions of cold ethanol, and drying on a steam bath, the product,B-'(1piperidy1) -p-methoxypropiophenone hydrochloride, M.P. 210-212, wasobtained.

B (l-piperidyl)-p-methoxypropiophenone hydrochloride (681 g.), 37%formaldehyde solution (292 g.), 95% piperidine (430 g.), and 2 liters ofethanol were refluxed for 1 hour. Most ofthe solvent was distilled offin vacuo while maintaining the inside temperature below 60. The residuewas cooled, and 2 liters of water and 300 ml. of 50% sodium hydroxidesolution were added." The mixture Was extracted with 2 portions of ether(800 ml. and 500 ml.). The combined ether extracts were dried C sodiumsulfate. The ether was then distilled off in vacuo without heating theresidue above 60. The residue was dissolved in 1100 ml. of petroleumether, and allowed to crystallize at 0. The product,3-(l-piperidyl)-2-(lpiperidylmethyl)-l-(4-rnethoxyphenyl)-1-propanone,was filtered and dried in the air, M.P. 54-57".

With stirring and cooling below 10, 50 g. of sodium borohydride wasadded to 400 ml. of methanol and 100 ml. of water. A cold solution of455 g. of 3-(1-piperidyl)- 2 (l piperidylmethyl) i 1 (4methoxyphenyl)-1-pro panone in 1 liter of methanol was then added over a25 minute period, with cooling below 10. After an additional 5 minutesof stirring in the cold, the ice bath was removed, 7 and stirring wascontinued with no further cooling. After 1 hour and 20 minutes, thereaction temperature rose to 33. Then, the mixture was warmed at 45-50for 2 hours. On cooling in 'an'ice bath, the crystalline base, 3-(1-piperidyl)-2-( 1-piperidylrnethyl)-1- (4-methoxypheny1)-1-propanol,was obtained. It was filtered, washed with dilute methanoLand dried invacuo over potassium hydroxide, M.'P. 88-91".

263 g. ofthe base obtained above was dissolved in 1300 ml. of ethanol,and the solution was acidified by the addition of a solution of hydrogenchloride in ethanol (500 ml. of 3.33 N) with cooling below 25. Thedihydrochloride was allowed to crystallizeat room temperature forseveral hours. After filtering, washing with two 100 ml. portions ofcold ethanol, and drying in vacuo over potassium hydroxide, 3-( 1piperidyl)-2- 1-piperidylmethy1) l-(p-methoxyphenyl)-l-propanoldihydrochloride, M.P.

to vary slightly according to -the rate of heating.

ExamplefS 4-acetylveratrole (60 g.) piperidine hydrochloride (40.6 g),paraformaldehyde .(15 g.), 60 ml. of ethanol, and 1 ml. of concentratedhydrochloric acid-were refluxed for 2 hours. The solution was filteredhot and allowed to crystallize in the cold. The product was filtered,washed with three 10ml. portions of cold ethanol, and dried in vacuoover potassium hydroxide to obtain 3-('l-piperidyl)-1-(3,4-dimethoxyphenyl) l -propanone hydrochloride, M.P. 180-182.

*3 l. piperidyl) 1 (3,4 dimethoxyphenyl) 1- propanone hydrochloride (10g.), 37% formaldehyde solution (3.88 g.), 95% piperidine (5.70 g), and50 ml. of ethanol were refluxed for 1 hour. The solvent was distilledoif in vacuo. Water (50 ml.) and excess 50% sodium hydroxide solutionml.) were added with cooling. The base was extracted with 2 portions ofether (50 ml. and 30 ml.). The combined ether extracts were dried oversodium sulfate, and concentrated in vacuo. The residue was redissolvedin 130 ml. of ether, and a solution of hydrogen chloride in ethanol wasadded to precipitate the solid 3-(1-piperidyl) -2-(1-piperidylmethyl)1-( 3 ,4-dimethoxyphenyl) -l-propanone dihydrochloride, melting at175-177". The mixed melting point with the starting material wasdepressed. On recrystallization from ethanol, the melting point rose to183-185".

3 (l piperidyl) 2 (1 piperidylmethyl) 1 (3,4-dimethoxyphenyl)-1-pr0panoue dihydrochloride (9.7 g.) was dissolved in80 ml. of water, and 5 ml. of 50% sodium hydroxide solution were added.The base was extracted with 100 ml. of ether. The ether was evaporatedin vacuo. The residual base was dissolved in 30 ml. of methanol andadded below 10 to a solution of 0.82 g. of sodium borohydride in 20 ml.of 50% methanol. The mixture was allowed to Warm to room temperatureduring 1 hour, and then warmed at 45-50" for 2 hours and 25 minutes.Most of the solvent Was distilled off in vacuo. Water (50 ml.) wasadded, and the mixture was extracted with ether (50 ml). After dryingwith sodium sulfate, the ether was evaporated in vacuo to leave3-(1-piperidyl)- 2 (1 piperidylmethyl) 1 (3,4 dimethoxyphenyl) 1-propanol as a crude residue.

The residue was dissolved in 20 ml. of ethanol, and acidified byaddition of a solution of hydrogen chloride in ethanol. The3-(1-piperidyl)2-(1-piperidylmethyl)-l- (3,4-dimethoxyphenyl)-l-propanoldihydrochloride, which crystallized at room temperature, was filtered,washed with ethanol, and dried in vacuo over potassium hydroxide, M.P.172-179". The dihydrochloride was solvated, and the melting point didnot improve on recrystallization.

The free base was obtained again by dissolving the dihydrochloride (1g.) in 20 m1. of water. Excess 10% sodium hydroxide solution was added,and the base was extracted with 30 ml. of ether. The ether was driedover sodium sulfate, and evaporated in vacuo. The residual oil wascrystallized from 3 ml. of petroleum ether to yield the base, M.P.64-66".

Example 6 Acetophenone (40 g.), morpholine hydrochloride (41.2 g.),paraformaldehyde g.), 60 ml. of ethanol and 1 ml. of concentratedhydrochloric acid were refluxed for 2 hours. The product,B-(4-morpholinyl)propiophenone hydrochloride, crystallized on cooling,M.P. 176-178".

fl-(4-morpholinyl)propiophenone hydrochloride (59.8 g.), 37%formaldehyde solution (28.5 g.), morpholine (40.7 g.) and 250 ml. ofethanol were refluxed for 1 hour. The solvent was distilled off invacuo. With cooling, 300 ml. of water and 40 ml. of 50% sodium hydroxidesolution were added. The mixture was extracted with 2 portions of ether(200 ml. and 100 ml). The combined ether extracts were Washed with 200ml. of water, dried with sodium sulfate, and evaporated in vacuo toleave a residual oil.

This crude base was dissolved in 300 ml. of ethanol, and acidified bythe addition of a solution of hydrogen chloride in ethanol. Thecrystalline product was filtered, washed with ethanol and dried in vacuoover potassium hydroxide to obtain 3-(4-morpholinyl)-2-(4-morpholinylmethyl)1-phenyl -1-propanone dihydrochloride, M.P.

3-(4-morpholiny1) -2-(4-morpholinylmethyl l-phenyll-propanone (50 g.)was dissolved in 300 ml. of water. Excess 50% sodium hydroxide solutionwas added, the base was extracted with 300 of ether, and the ether wasevaporated in vacuo. The residue was dissolved in 150 ml. of methanol,and the solution was added below 10 to 4.84 g. of sodium borohydride in40 m1. of meth- 6 anol plus 10 ml. of water. The reaction was allowed towarm to 35 After 1% hours, the reaction subsided, and the temperature ofthe mixture was maintained at 45-50" for 2% hours. Most of the solventwas distilled oif in vacuo, water (150 ml.) was added, and the oily basewas extracted with ether (150 ml). After drying over sodium sulfate, theether solution was concentrated in vacuo and the residue wascrystallized from ml. of methanol plus 100 ml. of water to yield3-(4-morpholinyl)-2-(4morpholinylmethyl)-1-phenyl 1 propanol, M.P.98-101".

A solution of 20 g. of the base in 100 ml. of ethanol was acidified bythe addition of a solution of hydrogen chloride in ethanol. Thecrystalline dihydroohloride melted at 237-238 Example 7o-Methoxyacetophenone (45 g.), piperidine hydrochloride (36.5 g.),paraformaldehyde (13.5 g.), 60 ml. of ethanol, and 1 ml. of concentratedhydrochloric acid were refluxed for 2 hours. After several days ofstanding in the refrigerator, the crystalline product was obtained. Itwas filtered, washed with ethanol and dried in vacuo over potassiumhydroxide to obtain [3 (1-piperidyl)-omethoxypropiophenonehydrochloride, M.P. 147-149".

5% l-piperidyl) -o-methoxypropiophenone hydrochloride (40 g.), 37%formaldehyde solution (17.2 g.), 95% piperidine' (25.2 g.), and 200 ml.of ethanol were refluxed for 1 hour. The solvent was distilled olf invacuo. With cooling, 200 ml. of water and 40 ml. of 50% sodium hydroxidesolution were added, and the base was extracted with ether (250 ml.).The ether solution was dried over sodium sulfate, and evaporated invacuo. The crude base thus obtained, 3-(1-piperidyl)-2-(lpiperidylmethyl)-1-(2-methoxyphenyl) 1 propanone, was dissolved in 1liter of dry ether, and hydrogen chloride gas was passed in toprecipitate the solid dihydrochloride. The crude dihydrochloride wasextremely hydroscopic, and was purified by dissolving it in 200 ml. ofethanol and adding 500 ml. of ether, to obtain crystalline 3-(1-piperidyl)-2-(l-piperidylmethyl)-1 (2-methoxyphenyl)- l-propanonedihydrochloride, M.P. 138-140".

3-(1-piperidyl) -2-(l-piperidylmethyl) 1 (Z-methoxyphenyD-l-propanonedihydrochloride (20 g.) was dissolved in water, excess 50% sodiumhydroxide solution was added, and the base was extracted with ether. Theether solution was evaporated in vacuo, the residual base was dissolvedin 50 ml. of methanol, and the solution added below 10 to 1.81 g. ofsodium borohydride in 40 ml. of methanol plus 10 ml. of Water. Themixture was stirred at room temperature for 1 hour and then for 2% hoursat 45-50". The mixture was concentrated by distilling olf part of thesolvent in vacuo, whereupon crystallization occurred. The :base,3-(1-piperidyl) 2 (l piperidylmethyl)-l-(2-methoxyphenyl)-l propanol,was allowed to crystallize in the cold, filtered, washed with 50%methanol, and dried in vacuo over potassium hydroxide to obtain the pureproduct, M.P. 88-91".

The free base obtained above was dissolved in ethanol (30 ml.), and thesolution was acidified by the addition of a solution of hydrogenchloride in ethanol. On standing, crystalline 3-1-piperidy1)-2-(l-piperidylmethyD-l- (2-rnethoxyphenyl)-1 propanoldihydrochloride, M.P. 138-151", was obtained.

Example 8 m-Methoxyacetophenone (25 g.), piperidine hydrochloride (20.3g.), paraformaldehyde (7.5 g.), 35 ml. of ethanol and 0.5 ml. ofconcentrated hydrochloric acid were refluxed for 2 hours. On cooling,crystalline fi-(lpiperidyl)-m-methoxypropiophenone hydrochloride, M.P.135-144", was obtained. Recrystallization from ml. of ethanol gave thepure material, M.P. 154.

/8-( 1-piperidyl) -m-methoxypropiophenone hydrochloride (18.5 g.), 95%piperidine (11.7 g.), 37% formalde 7 (p-tolyl) -'1-propanol,

hyde solution (7.92 g. and 90 ml. of ethanol were .re-

fluxed for 1 hour. The solvent was distilled off in vacuo.

.over anhydrous sodium sulfate, and the ether evaporated in vacuo. Thecrude base, 3-(1-piperidyl) -2-(1-piperidylmethyl) -1- (3 -methxyphenyl)-1 -propanone,

was dissolved in 30 ml. of ethanol and acidified by the addition of asolution of hydrogen chloride in ethanol. On addition of 100 ml. ofether, the crystalline dihydrochloride, M.P. 155-157", was obtained. 7

The base was obtained from 12.5 g. of 3-(1-piperidyl)-2-(l-piperidylmethyl)-1-(3-methoxyphenyl) 1 propanone dihydrochloride bydissolving it in water (100 ml.), adding excess 50% sodium hydroxidesolution, extracting with 2 portions of ether (80 ml. and 40 ml.), andevaporating the-ether in vacuo. The base was dissolved in 50 mLofmethanol and added below to 1.14 g. of sodium borohydride in 40 ml. ofmethanol and 10 ml. of Water. The mixture was allowed to warm to roomtemperature with stirring during 1 hour, and then warmed at 45-50 for 2%hours. Most of the solvent was distilled off in vacuo. Water (50 ml.)was added to the residue, and the base was extracted with ether (250ml). On evaporating the ether in vacuo, the solid base, 3-(1-piperidyl)-2-(1-piperidylmethyl)-l-(3 methoxyphenyl)- l-propanol, M.P.103-105", was obtained. Recrystallization from methanol gave 'a productmelting at 105- 106.5". A solution of 8 g. of the free base obtainedabove in 20 m1. of ethanol was acidified by addition of a solution ofhydrogen chloride in ethanol. Onaddition of 40 ml. of ether, thecrystalline dihydrochloride was obtained. The dihydrochloride wassolvated, and the melting point depended upon the rate of heating. Asample, heated very slowly in the apparatus, melted at 208-212, afterslight preliminary shrinking.

Example 9 Methyl p-tolyl ketone (40.2 g.), piperidine hydrochloride(36.5 g.), paraformaldehyde 13.5 g.), 60 ml. of ethanol, and 1 ml. ofconcentrated hydrochloric acid were refluxed for 2 hours. On cooling,crystalline 3-(1-piperidyl)-l-(p-tolyl)-1 propanone hydrochloride, M.P.172.5- 174.5 was obtained. V I i 3( l-piperidyl) -l-'(p-tolyl)-1-propanone hydrochloride (45 g.),,.9.5% piperidine (30.1 g.),.37%,formal'del 1-yde fsolution' (20.4 g.), and 200 ml. of ethanol wererefluxed for lhour. The solvent was distilled off in vacuo. Withcooling, 200 mLof water and 40 ml. of 50% sodium hydroxide solution wereadded, and the base was extracted with 2 portions of ether (150 ml. and75 ml.) The combined ether extracts were dried over sodium sulfate andevaporated in vacuo. The solid residue was crystallized from a mixtureof 125 ml. of methanol and 34 ml. of water to give practically pure3-(1-piperidyl)-2 (l-piperidylmethyl)-1-(p-tolyl)-1-propanone, M.P.70-72.. I

3 (1 piperidyl) 2.- (1 piperidylmethyl) -1 (ptolyl)-1-propanone (20 g.)Was'dissolved in 80ml. of

'methauol, and the solution was added below 10 to a solution of 2.30 g.of sodium borohydride, 40 ml. of methanol, and 101111; of water during20 minutes. After an additional five minutes in the cold, the mixturewas allowed to warm with stirring to room temperature during '1 hour. Ihe temperature reached 32 before the reaction subsided. The mixture waswarmed for 2 hours at 45-50".

Upon. the addition of 18ml. of water and cooling, the

crystalline base, 3-(1 piperidyl) -2 l-piperidylmethyl) -1- M.P. 68-71,wasiobtained. The base (12.3 g.) in ethanol '(25 ml.) was acidified 'bythe addition cat a solution of hydrogen chloride in ethanol (35 ml. ofapproximately 3 N). Ether (200 ml.) was added to give, the crystallinedihydrochloride, M.P.

Cir

.Eixamp'le 10 i m-Chloroacetophenone (26.5 g.), piperidine hydrochloride(20.8 g.), paraformaldehyde (7.7 g.), ethanol (35 ml.), and 0.6 ml. ofconcentrated hydrochloric acid were refluxed for 2 hours. On cooling,crystalline 5-(1- piperidyl)-m-chloropropiophenone hydrochloride, M.P.180-182", was obtained.

;3-( lpiperidyl -m'chloropropiophenone hydrochloride (25.2 g.),piperidiue (15.7 g.), 37% formaldehyde solution (-10.7g.) and ml. ofethanol were refluxed for 1 hour. The solvent was distilled off invacuo. With cooling, 125 ml. of water and 20 m1. of 50% sodium hydroxidesolution were added. The mixture was extracted with ml. of ether. Theether extract was dried over sodium sulfate and evaporated in vacuo toobtain the crude product, 3 (1 piperidyl) 2 (1 piperidylmethyl) 1-(3-chlorophenyl)-l-propanone, which was reduced directly with sodiumborohydride.

Sodium borohydride (3.3 g.) was dissolved in 50 ml. of methanol plus 15ml. of Water, below 10. 'A cold solution ofthe crude ketone obtained asdescribed above in 200 ml. of methanol was added below 10, over a 15minute period. The mixture was stirred for 1 hour while warming to roomtemperature and 20 minutes at 50. On cooling, 16.9 g. of crystalline3-(1-piperidyl)-2-(1- piperidylmethyl) 1 (3 chlorophenyl) 1 propanol,M.P. 9699, was obtained. Y

The base (10 g.) was dissolved in 30 ml. of ethanol, and a solution ofhydrogen chloride in ethanol was added.

, The 3-(l-piperidyl)-2-(l-piperidylmethyl) 7 1 (3-chloro- Hydrogenchloride gas was passed into a solution of 39.3 g. of pyrrolidine in 100ml. of ethanol, until the mixture was just slightly acidic. :Then, 83 g.of p-methoxyacetophenone, 24.9 g. of paraformaldehyde, and 1 ml. ofconcentrated hydrochloric acid were added. The mixture was refluxed for2 hours. On cooling, crystalline fl-(lpyrrolidyl)-p-methoxypropiophenonehydrochloride was obtained, melting at -182. i v

' fi-( l-pyrrolidyl)-p-methoxypropiophenone hydrochloride (45 g.),pyrrolidine (24 g.), 37% formaldehyde solution (20 g.), and 20 ml. ofethanol were refluxed for 1 hour. The solvent was distilled oil invacuo. With cooling, 200 ml. of water and 40 ml. of 50% sodium hydroxidesolution were added to the residue. Thebase solidified, was crushed,filtered, and washed with water. Without drying, the crude base wasdissolved in 125 ml. of methanol at room temperature, and water (85ml.).added to slight turbidity. On cooling, crystalline. BH-pyrrolidyl)- 2 -(-1'- pyrrolidylmethyl) 1 (4 methoxyphenyl) 1-propanone, melting at 8688, was obtained.

Sodium borohydride (2.40 g.) was dissolved in 40 ml. of methanol and10ml. of water below 10. A solution were added to the residue. fIhepetroleum ether was evaporated in vacuo to leave a viscous, partlycrystalline residue, 3 (1 pyrrolidyl) 2 (-1 pyrrolidylmethyl).-

The crude base obtained as described abovewas dissolved in 200 m1. ofether. A solution of hydrogen chloride in ethanol was added. Aftersettling in the cold, the

supernatant liquid was decanted, and the gum crystallized from 50 ml. of'isopropanol to obtain. 3-(l-pyrrolidyl)-2- panol .dihydrochloridemelting at 191-194. Recrystallization raised the melting point'to199-201.

9 Example 12 p-Methoxyacetophenone (50 g.), dimethylamine hydrochloride(35.3 g.), paraformaldehyde (15 g.), 70 ml. of ethanol and 0.7 ml. ofconcentrated hydrochloric acid were refluxed for 2 hours. While cooling,200 ml. of acetone were added. The crystalline product,fl-dimethylamino-p-methoxypropiophenone hydrochloride, M.P. l82-184, wasseparated by filtration.

B-Dimethylamino p-methoxypropiophenone hydrochloride (68 g.), 25%dimethylamine in water (101 g.), 37% formaldehyde solution (34 g.) and300 ml. of ethanol were refluxed for one hour. The solvent wasevaporated in vacuo. The residue was chilled and 300 n11. of water and40 ml. of 50% sodium hydroxide solution were added below 20. The mixturewas extracted twice with ether (250 ml., of 100 ml.), the ether extractswere combined and dried over sodium sulfate. The ether was thenevaporated in vacuo and the crude residue was crystallized from 210 ml.of petroleum ether. The 3-dimethylamino-2-dimethy1aminomethyl-1-(4-methoxyphenyl)-1-propanone melted at 5461.

Sodium borohydride (6.87 g.) was dissolved in 20 ml. of water and 60 ml.of methanol below 3-dimethylamino-2 dimethylaminomethyl-l(4-methoxyphenyl)- l-propanone (48 g.) was dissolved in 100 ml. ofmethanol and added to the sodium borohydride solution over a 10 minuteperiod below 10. The mixture Was stirred while cold for 10 minutes, then1 hour and minutes at room temperature and 2% hours at 4550. The solventwas distilled in vacuo. 200 ml. of Water were added to the residue. Thiswas extracted with 200 ml. of ether and the ether extracted was driedover sodium sulfate. Then the solvent was evaporated in vacuo. Theresidue was dissolved in 200 ml. of ethanol and acidified with asolution of hydrogen chloride in ethanol. 3-dirnethylamino 2dimethylaminomethyl-l- (4-methoxyphenyl) l-propanol dihydrochloridecrystallized. The product was recrystallized from ethanol, M.P.2265-227".

10 We claim: 1. A compound selected from the group consisting of basesrepresented by the formula R ()H R 1 wherein R represents a member ofthe group consisting of hydrogen, halogen, lower alkyl and lower alkoxy,and the symbols R represent a member of the group consisting of loweralkyl individually, and collectively, together with the nitrogen atom,pyrrolidyl, piperidyl, and morpholinyl and pharmacologically acceptableacid addition salts thereof.

2. A compound represented by the formula 2,514,380 Duschinsky July 11,1950 2,835,676 Sprague et a1 May 20, 1958 2,962,501 Cutler et a1 Nov.29, 1960 OTHER REFERENCES Cardwell: Journal of the Chemical Society,1950, page Williams et al.: Journal of the American Chemical Society,vol. 74, 3875 and 3876 (1952).

Hach et a1.: Chemical Abstracts, vol. 51, page 10403]: (1957).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORECTION atent No, 8,058,987October 16 1962 Harry Allen Albrecht et ale It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 2, line 10, for "'posphate" read phosphate 9 :olumn 6, line 38,for "hydroscopic" read hygroscopic :olumn 9, line 16, strike out "of";column l0 lines 4 to 7 ;he right-hand portion of the formula shouldappear as shown elow instead of as in the patent:

.ines 22 to 24, the center portion of the formula should appear 15 shownbelow instead of as in the patent:

ame column 10 under the heading 'UIJITED STATES PATENTS" dd thefollowing:

2,934,534 Morren mew-w) Apr. 26 1960 ame column 10, above "OTHERREFERENCES insert:

FOREIGN PATENTS 840,496 Great Britain July 6 1960 Signed and sealed this21st day of May 1963 SEAL) ttest:

RNEST W, SW-IDER 7 DAVID L, LADD ttesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES REPRESENTED BYTHE FORMULA
 3. A COMPOUND REPRESENTED BY THE FORMULA